Editors' ChoiceCancer

Deciphering the Signatures of Bone Metastases

Science Signaling  22 Oct 2013:
Vol. 6, Issue 298, pp. ec257
DOI: 10.1126/scisignal.2004831

Breast cancer commonly metastasizes to the bone, where tumor cells cause pathological bone loss by activating osteoclasts, cells that degrade bone. Ell et al. found that a protein secreted by metastatic cancer cells decreased the abundance of microRNAs (miRNAs) that inhibited osteoclast development. Mouse pre-osteoclast RAW264.7 cells cultured with conditioned media from highly metastatic breast cancer cells showed increased differentiation into osteoclasts compared with those cultured in conditioned medium from weakly metastatic cells. Differentiated cells had an altered miRNA expression profile that correlated with those induced by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), which promotes osteoclast differentiation. A subset of miRNAs that were increased in RAW264.7 cells exposed to conditioned medium from metastatic cells was also increased in the serum of mice with bone-metastatic tumors. Two of these increased miRNAs, miR-16 and miR-378, were also increased in the serum and bone metastases from breast cancer patients compared with their abundance in either healthy donor serum or the patients’ primary tumors. Of the 45 miRNAs that were decreased in abundance, miR-33a, miR-133a, miR-141, miR-190, and miR-219 were also decreased in differentiated primary human osteoclasts and specifically targeted osteoclast-related mRNAs. Ectopic expression of these five miRNAs inhibited RANKL-induced differentiation of pre-osteoclasts and reduced their bone-resorbing capacity when seeded onto bovine bone. Systemic injection of miR-141 or miR-219 increased hind limb bone density and decreased the number of osteoclasts in healthy mice without affecting that of osteoblasts (the bone-forming cell type). Injection of miR-141 or miR-219 also decreased bone lesions in mouse models of bone metastasis, indicating that the repression of key miRNAs is critical to metastatic bone colonization and destruction. Among a panel of growth factors and cytokines, only the abundance of soluble intercellular adhesion molecule 1 (sICAM1) was consistently increased in both the conditioned medium from metastatic breast cancer cells and the serum of bone-metastatized breast cancer patients compared with sICAM1 abundance in nonmetastatic cells and serum of metastasis-free breast cancer patients, respectively. sICAM1 had an additive effect on RANKL-induced maturation of RAW264.7 cells and repression of miR-33a, miR-133a, miR-141, miR-190, and miR-219 abundance in RAW264.7 cells. Conversely, antibodies against ICAM1 or β2-integrin (an ICAM1 receptor) inhibited NF-κB activation and the bone-resorbing capacity of RAW264.7 cells exposed to conditioned medium from metastatic cell lines. Consistent with a role for NF-κB, pharmacological inhibition of the NF-κB activating kinase IKK abrogated sICAM1-induced miRNA repression. Thus, by secreting sICAM1, metastatic tumor cells activate NF-κB signaling that silences miRNA-mediated inhibition of osteoclast maturation, which results in pathological bone destruction (see Waning et al.).

B. Ell, L. Mercatali, T. Ibrahim, N. Campbell, H. Schwarzenbach, K. Pantel, D. Amadori, Y. Kang, Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24, 542–556 (2013). [PubMed]

D. L. Waning, K. S. Mohammad, T. A. Guise, Cancer-associated osteoclast differentiation takes a good look in the miR(NA)ror. Cancer Cell 24, 407–409 (2013). [PubMed]